Chapter 1: Bibliographic Synthesis
2. The inflammasome, a primordial complex of innate immunity
2.4. IL-1β
2.4.1 The maturation of IL-1β
The concept of interleukin (IL) appeared in 1979 and has defined a protein capable of acting as a communication signal between different populations of leukocytes (A. DINARELLO, 2017;
DINARELLO, 2009a). IL-1 family members are responsible for severe attacks in the context of systemic or local inflammation and contribute for many chronic diseases (CHEN et al., 2017a).
Inflammatory processes related to a dysregulated production of IL-1 are involved in the pathophysiology of several common diseases such as atherosclerosis, osteoarthritis, metabolic syndromes and type 2 diabetes (type 2 diabetes or type 2 diabetes mellitus) (A.
DINARELLO, 2017). However, numerous biological properties of the IL-1 family are still non- specific (DINARELLO, 2018a).
Currently, there are 11 members of the IL-1 family (IL-1α, IL-1β, IL-1Rα, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, and IL- IL-38) (GUAN; ZHANG, 2017), and 10 members of the IL-1 family of receptors (IL-1R1 to ILR10) (BORASCHI et al., 2018). Among the IL-1 family, IL-1β, also known as IL-1F2, is one of the most characterized. It is considered as a key pro-inflammatory cytokine, mainly produced by myeloid cells, inducing the physiological, hematological, metabolic and immunological characteristics of the host after infection, trauma or immunological activation (DINARELLO, 2018a).
The gene structure, expressional regulation, and function of IL-1β are evolutionarily well conserved (PALOMO et al., 2015), and gene encoding it is not constitutively expressed (DINARELLO, 2018a; YIN et al., 2009; ZHU; KANNEGANTI, 2017). Thus, in response to endogenous or exogenous inflammatory agents, such as Toll-like receptor (TLRs) ligands, which are responsible for the recognition of a host of PAMPs, IL-1β is synthesized as a pro- cytokine (pro-IL-1β), having a molecular weight of 31-kDa. Pro-IL-1β is then cleaved by caspase-1 at two sites related to the sequence: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2) with a molecular weight of 17.5-kDa, resulting in mature IL-1β generation (AFONINA et al., 2015; AMARANTE-MENDES et al., 2018; CAMERON et al., 1985; CERRETTI et al., 1992;
DINARELLO, 2018a; GUARDA; SO, 2010; KWAK et al., 2016; SCHRODER; TSCHOPP, 2010). Pro-IL-1β accumulates in the cytosol (SEMINO et al., 2018; STOFFELS et al., 2015).
IL-1β maturation can occur through two possible levels of activation: One induced by NF-κB- mediated leading to pro-IL-1β expression and the second option by of the proteolytic cleavage of caspase-1 and subsequent maturation of pro-IL-1β (NAIK; DIXIT, 2010; YANG et al., 2019).
Studies indicate that caspase-8 might be able to cleave pro-IL-1β during immune responses (LATZ; XIAO; STUTZ, 2013b).
The cleavage and thus maturation of IL-1β also appear to take place out of the cell and could involve other proteases that can cleave IL-1β but are present in the extracellular inflammatory environment (GIULIANI et al., 2017; LOPEZ-CASTEJON; BROUGH, 2011; STEHLIK, 2009).
Extracellular processing of pro-IL-1β is not novel and other proteases derived from neutrophils and mast cells have been implicated to be present in pro-inflammatory environments (AFONINA et al., 2015; BENT et al., 2018; DAUTOVA et al., 2018). Several studies have reported that exosomes were involved in the transfer of fully functional cytokines and growth factors (COSSETTI et al., 2014; DAUTOVA et al., 2018; WEBBER et al., 2010).
2.4.2 Excretion of IL-1β
The excretion process of IL-1β is not fully understood. Several secretory pathways have been proposed: exocytosis of granules derived from lysosomes; the release of exosomes derived from multi-vesicular bodies and the release of microparticles from the plasma membrane (ANDREI et al., 1999; DI VIRGILIO, 2013).
IL-1β secretion is also strongly associated with autophagy, an unconventional process (DANIELS; BROUGH, 2017). This process is independent of the endoplasmic reticulum and the Golgi apparatus and involves the autodigestion function of the cells by autophagy, which leads to the release of cellular content (DANIELS; BROUGH, 2017; KURODA et al., 2001).
The role of autophagy in IL-β secretion is complex. Several studies suggest a tonic inhibition of IL-1β secretion both by the degradation of pro-IL-1β and by the negative regulation of inflammasome NLRP3 (HARRIS et al., 2011). However, additional research proposes that mature IL-1β is actively packaged in vesicles and secreted after autophagy stimulation (DUPONT et al., 2011; GUAN; ZHANG, 2017).
30 2.4.3 The regulation of IL-1β
IL-1β participates in most events involved in the activation and regulation of inflammatory response (CHEN et al., 2017a). IL-1β can stimulate other cytokines such as IL-6, TNF-α, IL- 1α, granulocyte macrophage colony-stimulating factor (GM-CSF), and granulocyte-colony stimulating factor (G-CSF) (BHATTACHARYA et al., 2015; DINARELLO, 2018a;
SÖDERQUIST et al., 1995). It is also implicated in the release of neutrophils (polymorphonuclear cells), activation of lymphocytes, differentiation of Th17 cells and activation of dendritic cells (BENT et al., 2018; COSTA et al., 2019; PELLETIER et al., 2010).
IL-1β also plays a role in the secretion of vascular endothelial growth factor (VEGF), reactive oxygen species (ROS) and reactive nitrogen species (RNS) (PAPIEWSKA-PAJĄK et al., 2017;
ROBERTS et al., 2010). IL-1β is an essential cytokine for the host immune system as it also participates in the activation and differentiation of T cells, B cells and natural killer (NK) cells (CHEN; KANG; FU, 2018; CRUVINEL et al., 2010; LUIS MUÑOZ-CARRILLO et al., 2019).
This proinflammatory mediator is generated at lesion sites and coordinates the recruitment of leukocytes to neutralize and phagocyte pathogens, being one of the first cytokines to be secreted during the early stages of inflammation (CHEN; KANG; FU, 2018; CRUVINEL et al., 2010; SCHRODER; TSCHOPP, 2010).
Furthermore, IL-1β, IL-6 and tumor necrosis factor α (TNFα) are considered the most important cytokines of inflammation in bone physiology and pathology (KWAN TAT et al., 2004; ROMAS;
GILLESPIE; MARTIN, 2002). The balance of cell activity, such as osteoblasts that are located on the bone surface and are derived from mesenchymal progenitors (BLAIR, 1998), and osteoclasts that are multinucleated cells derived from the myeloid lineage (BLAIR et al., 1989), has been reported as essential for the maintenance of bone homeostasis and its renewal. Any imbalance in the relative levels of activity of these two cell types may induce bone pathology (HENDERSON; NAIR, 2003). S. aureus infection can cause such imbalance, mediated in part by the inflammatory response (RASIGADE et al., 2013).
Osteoblasts and osteoclasts interact permanently. The osteoblasts can identify different danger signs and modulate the differentiation and activity of osteoclasts (HENDERSON; NAIR, 2003; MATSUO; IRIE, 2008). A key interaction in the regulation of osteoclastogenesis occurs between the receptor activator of nuclear factor kappa B (RANK) expressed by osteoclast precursors and its ligand-expressed RANKL by osteoblasts (LIU; ZHANG, 2015; LORENZO;
HOROWITZ; CHOI, 2008; ROGGIA et al., 2001; ROMAS; GILLESPIE; MARTIN, 2002).
In this context, IL-1β stands out as a strong stimulator in vitro and in vivo of bone resorption through the regulation of RANKL that stimulates osteoclastogenesis (LUO et al., 2018;
RUSCITTI et al., 2015). Thus, IL1β plays a predominant role in the regulation of bone remodeling, and that any disturbance of the expression levels of this cytokine may lead to an imbalance in bone remodeling homeostasis in favor of osteoclastogenesis and bone resorption activity and bone mineralization and production by osteoblasts, eventually leading to the destruction of bone tissue (DINARELLO, 2009b; RASIGADE et al., 2013; YANG et al., 2019).